JP2001192069A - Package for container filled with chemicals containing bicarbonate - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a package for container filled with chemicals which prevents chemicals containing bicarbonate from transforming without enclosing carbonic acid gas and improves safety and stability for the chemicals containing bicarbonate. SOLUTION: The package for container filled with chemicals containing bicarbonate is in a structure wherein a plastic container filled with chemicals containing bicarbonate is packed in a gas-nonpermeable packaging material, a space between the plastic container and the packaging material is made to be a nitrogen gas ambience or an air ambience wherein a carbonic acid gas is positively nonexistent, and a deoxidizer producing a less amount of carbonic acid gas and an oxygen detecting agent are housed in the space.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a package for packaging a container filled with a bicarbonate-containing chemical solution. More specifically, a container filled with the bicarbonate-containing chemical solution is packaged in a gas-impermeable packaging material, and pinhole generation of the packaging material is detected, and the stability of the bicarbonate-containing chemical solution is determined. The present invention relates to a bicarbonate-containing chemical liquid-filled container package which maintains the above-mentioned properties and maintains the efficacy of the oxygen detector.

[0002]

BACKGROUND OF THE INVENTION The most important role of artificial kidney therapy, such as hemodialysis, hemofiltration, hemofiltration dialysis and peritoneal dialysis, is the correction of metabolic acidosis, as well as the removal of water and metabolites. The dialysate used in these procedures all contained a buffer (alkalizing agent), and in hemodialysis the bicarbonate in the form of sodium bicarbonate was the original buffer. However, sodium bicarbonate solution reacts at room temperature to form carbon dioxide gas, changes its concentration, easily reacts with calcium ions contained as other electrolyte components, etc., and causes difficulties in formulation such as precipitation. Thus, other buffers, such as lactate or acetate, have been used in their place. Lactate or acetate is metabolized to bicarbonate in the body to exert a buffering action. However, when a drug solution containing lactate or acetate is administered to patients with metabolic abnormalities due to major surgery such as liver injury, diabetes, or surgical invasion, or severe patients such as acute renal failure or multiple reservoir failure, acetic acid intolerance occurs. There are problems such as side effects such as lowering of blood pressure and bad mood due to poor mood and the effect of correcting acidosis is low.In recent years, instead of lactate, bicarbonate is used again as a buffer for the blood. Hemodialysis fluid, hemofiltration replacements are being used.

[0003] The chemical containing bicarbonate is usually
It is an aqueous solution containing sodium bicarbonate, and contains an electrolyte or saccharides as necessary. In such a chemical solution containing bicarbonate, sodium bicarbonate is generally decomposed into sodium carbonate and carbon dioxide gas. As the decomposition reaction progresses, carbon dioxide gas in the filled chemical is released, and p of the chemical is released.
H rises. When a bicarbonate-containing drug solution having such an increased pH is administered to a patient, metabolic acidosis, which is an essential function, is not corrected, but rather there is a risk of side effects, and the intended purpose is not achieved.

On the other hand, when a gas-impermeable glass container is used as a container for filling a bicarbonate-containing solution,
The gas generated by decomposition does not go out of the reaction system, is absorbed again by the chemical solution, and the pH is stable. However, glass containers are heavy, are easily damaged, and are difficult to handle. Therefore, glass containers have recently been replaced with plastic containers. As a plastic container is usually made of a material with high gas permeability, filling this container with a bicarbonate-containing chemical solution reabsorbs the carbon dioxide gas generated during heat sterilization or during long-term storage. Without being released from the container wall, the pH of the chemical solution changes. For this purpose, it is common practice to package a container filled with the chemical solution with a gas-impermeable packaging material to prevent a change in the chemical solution due to the release of carbon dioxide gas.

[0005] However, when a pinhole occurs in the gas impermeable packaging material, the carbon dioxide gas released from the container wall is further released to the outside of the packaging material, and the pH of the chemical solution filled in the container also rises. In addition, changes such as a decrease in the content of bicarbonate due to the release of carbon dioxide gas occur. If such a drug solution is incorrectly administered, there is a concern about the risk of side effects. Therefore, between the container and the packaging material, oxygen detector, pH
It is necessary to introduce a pinhole checker such as an indicator that changes color due to a change (Japanese Patent Laid-Open No. 8-164185).
JP, JP-A-11-139461, WO97 / 48365, etc.).
Further, in order to maintain the effectiveness of the oxygen detector, it is necessary to use a deoxidizer in combination (Japanese Patent Application Laid-Open No. 8-164185).

However, when iron powder-based oxygen absorbers, which are generally used as oxygen absorbers, are used, the carbon dioxide gas released from the bicarbonate is absorbed by activated carbon and iron, which are the main components of the oxygen absorber. In addition, problems such as the inability to maintain the stability of the bicarbonate-containing solution occur. Therefore, as a measure for increasing the stability of the bicarbonate-containing chemical solution, a certain concentration of carbon dioxide gas is sealed in the space between the container and the packaging material (Japanese Patent Laid-Open No. 61-355, Japanese Patent No. 2750373, Patent Nos. 2811035 and 2890142), and at present, a carbon dioxide-generating type oxygen scavenger is used (Japanese Patent No. 2527532, Japanese Patent No. 27505329, Japanese Patent No. 2890142). .

However, when encapsulating carbon dioxide in the space between the bicarbonate-containing drug-filled container and the packaging material, it is necessary to pay particular attention to the concentration of carbon dioxide to be enclosed. There is a problem in that the pH of the filled chemical decreases and the bicarbonate content in the chemical increases. In addition, when a carbon dioxide-generating type deoxidizer is introduced into the space, and packaging is performed while the space is in a normal air state, the amount of oxygen absorbed corresponds to the amount of oxygen absorbed due to the characteristics of the oxygen absorber. An amount of carbon dioxide is released, causing a drop in the pH of the drug solution and an increase in bicarbonate content. Therefore, in order to maintain the stability of the chemical solution, a method such as using a carbon dioxide gas absorbent or enclosing nitrogen gas in the space between the container and the packaging material to minimize the amount of oxygen is used. (JP-A-8-164185).

As described above, when a carbon dioxide-generating type oxygen scavenger is introduced into the space between the container filled with the bicarbonate-containing chemical solution and the packaging material, a large amount of carbon dioxide gas depends on the capacity of the space. In order to maintain the stability of the drug solution generated and filled in the container, complicated operations such as introducing a carbon dioxide gas absorbent and adjusting the pH and bicarbonate content of the filled drug solution are necessary. Becomes Further, when carbon dioxide gas is sealed in the space between the liquid medicine filling container and the packaging material, there is a disadvantage that the pH tends to fluctuate in the initial stage of storage due to the variation in the amount of sealing.

[0009]

SUMMARY OF THE INVENTION An object of the present invention is to enhance the safety of a bicarbonate-containing chemical by enclosing an oxygen detector as a pinhole checker for packaging materials and to stabilize the bicarbonate-containing chemical. It is an object of the present invention to provide a chemical-filled container package capable of preventing a change in a bicarbonate-containing chemical solution without enclosing carbon dioxide gas in order to enhance the property.

[0010]

Means for Solving the Problems As a result of various studies to achieve the above object, the present inventors have filled a plastic container with a bicarbonate-containing chemical solution, and placed it in a gas-impermeable packaging body. By using a container package in which a catechol-type oxygen absorber and an oxygen detector are enclosed as an oxygen absorber together with the container, the space between the container and the packaging material is not actively filled with carbon dioxide from outside. However, they have found that it is possible to maintain the stability of the filled chemical solution and the efficacy of the oxygen detector for a long period of time, and have reached the present invention.

That is, according to the present invention, a plastic container filled with a chemical solution containing bicarbonate is packaged in a gas-impermeable packaging material, and the space between the plastic container and the packaging material is positively increased by carbon dioxide gas. A bicarbonate-containing chemical liquid-filled container package having an atmosphere in which the concentration is not adjusted and further containing a deoxidizer and an oxygen detector in the space.

According to another aspect of the present invention, a plastic container filled with a chemical solution containing bicarbonate is packaged in a gas-impermeable packaging material, and the space between the plastic container and the packaging material is There is a bicarbonate-containing chemical liquid-filled container package in which a nitrogen gas atmosphere or an air atmosphere in which carbon dioxide gas does not actively exist, and in which a deoxidizer and an oxygen detector are contained in the space.

In one embodiment of the present invention, the plastic container is a multi-chamber container, and the bicarbonate-containing chemical solution is a bicarbonate solution (pH: 7.6 to 8.6). A) and a solution (B) containing an electrolyte and / or a reducing sugar having a pH of 3.0 to 5.0, and a pH of 7.0 when the solution (A) and the solution (B) are mixed. 0
薬 7.6, characterized in that the solution (A) is filled in one chamber and the solution (B) is filled in another chamber in the multi-chamber container.

[0014]

BEST MODE FOR CARRYING OUT THE INVENTION The chemical solution of the present invention is a bicarbonate-containing chemical solution, for example, a bicarbonate-containing chemical solution having a pH of 7.0 to 7.6, preferably a pH of 7.6. ~ 8.6
(A) and a solution (B) containing an electrolyte and / or a saccharide and having a pH of 3.0 to 5.0. The solution (A) and the solution (B) were mixed. PH at that time is 7.0 to 7.6. The solution (A) used in the present invention contains a bicarbonate and, if necessary, an electrolyte and / or a saccharide. As the bicarbonate, those conventionally used for various dialysates and electrolyte infusions may be used. The bicarbonate may be a single aqueous solution of sodium bicarbonate such as sodium bicarbonate or potassium bicarbonate, or a mixture thereof. It is possible to include electrolyte ions and sugars other than salts. Here, examples of the electrolyte ion include a sodium ion and a potassium ion that do not generate an insoluble salt by reacting with bicarbonate. Examples of the saccharide include glucose, xylitol, and sorbitol, and glucose, which is a reducing sugar, is particularly preferable. Further, polyhydric alcohols such as glycerol can be used.

The solution (B) prepared in the present invention is a solution containing at least cations such as calcium and magnesium, and further contains electrolyte ions and saccharides other than calcium and magnesium,
For example, it can contain a reducing sugar.

As the electrolyte used in the present invention, any of those conventionally used can be used. For example, sodium chloride, sodium acetate, sodium citrate, potassium chloride, potassium iodide, potassium citrate, acetic acid Potassium, calcium citrate, calcium glycerophosphate, calcium gluconate, magnesium sulfate, magnesium chloride and the like can be mentioned.

In the production of the solution (A) in the present invention, the pH is usually 7.6 to 8.6, preferably 7.
It is adjusted to 9 to 8.5, most preferably 8.1 to 8.3.

The solution (B) used in the present invention contains a reducing sugar and an electrolyte. These solutions are prepared according to a conventional method, and the pH is usually adjusted to 3.0 to 5.0, preferably 3.7 to 4.3, and most preferably 3.9 to 4.1.

The container used in the present invention is not particularly limited in its shape and thickness, but is a plastic container having one or more chambers having a chemical liquid inlet and a chemical liquid outlet, for example, a bag. In particular, a flexible plastic container having a plurality of chambers is preferred. The material is conventionally used polyolefin resin such as polypropylene and polyethylene, and general thermoplastic resin including polyvinyl chloride resin.It is highly safe for medical use and at least when high-pressure steam sterilization is performed. Those that withstand a temperature of 105 ° C. are desired. In the present invention, the gas permeability of the container is not particularly limited. In a container having a plurality of chambers, all or a part of a partition wall between the chambers can be separated and opened from the outside of the container, and is formed by a separating and opening means that allows communication between the chamber and the chamber. This is a medical plastic container. In addition, the means capable of separating and opening is formed by inserting a member for lowering the adhesive strength in the adhesive portion, or having a lower adhesive strength than the portion where the container peripheral portion is welded. .

Further, the gas impermeable packaging material for accommodating these containers is, for example, ethylene vinyl alcohol copolymer (EVOH), polyethylene terephthalate (PE).
T) Packaging materials composed of polyvinylidene chloride (PVDC), nylon, etc., packaging materials obtained by subjecting these materials to vapor deposition of a gas barrier material such as silica or alumina, or multilayer films combining these materials Can be used. The gas impermeable here, usually oxygen permeability 10 ml / m ^2/24 hours / 1 atmosphere or less, preferably as long as also the following 1 ml / m ^2/24 hours / 1 atm. In addition, it is desirable to use a packaging material that has transparency so that the discoloration of the oxygen detector can be confirmed and is liquid-impermeable.

The container package of the bicarbonate-containing chemical solution used in the present invention encloses an oxygen detecting agent and a deoxidizing agent when the plastic container filled with the chemical solution is accommodated in a gas-impermeable packaging material. The space preferably has a larger space around it so that the oxygen absorbing effect of the oxygen scavenger can be easily exerted. The oxygen detector is not particularly limited as long as it changes its physical properties in the presence of oxygen. Preferably, the oxygen detector has a color change due to the presence of oxygen, for example, Ageless Eye manufactured by Mitsubishi Gas Chemical Co., Ltd. Is exemplified. Further, as the oxygen scavenger, there is preferably an oxygen scavenger having a small carbon dioxide gas generation amount, for example, a catechol-based oxygen scavenger. Specifically, the carbon dioxide gas fraction is 1.
There is an oxygen scavenger that is 0-8.0 vol%. Examples of such an oxygen scavenger include “Tamotsu D” and “Tamotsu V” manufactured by Oji Chemical Industries, Ltd.

As for the gas state in the space, it is preferable to replace the air in the space with nitrogen in order to promptly change the color of the oxygen detector. However, even in the air state where the nitrogen gas is not replaced in the space, the capacity of the space is adjusted, and a catechol-based oxygen absorber that generates and absorbs a small amount of carbon dioxide gas is enclosed as an oxygen absorber. And wrap it. Examples of such oxygen absorbers include the above-mentioned catechol-based oxygen absorbers, for example, “Tamotsu D” and “Tamotsu V” manufactured by Oji Chemical Industries, Ltd.

In the present invention, a plastic container filled with a chemical solution containing bicarbonate is packaged in a gas-impermeable packaging material, and the space between the plastic container and the packaging material is positively adjusted for carbon dioxide gas concentration. It is characterized by an atmosphere in which no nitrogen gas is applied, and one embodiment thereof is a nitrogen gas atmosphere or an air atmosphere in which carbon dioxide gas does not actively exist. By setting the atmosphere in which the carbon dioxide concentration is not actively adjusted, it is possible to prevent the bicarbonate content from decreasing and the pH from increasing. In addition, if a pinhole occurs in the packaging material during storage due to the oxygen detector being contained in the space, even if a decrease in the bicarbonate concentration and an increase in the pH of the chemical solution occur, it can be detected in advance. It is possible. Further, the presence of the oxygen scavenger in the space makes it possible to maintain the effectiveness of the oxygen sensing agent. In addition, by using a two-chamber container as the chemical liquid filling container, the stability of bicarbonate and reducing sugar is increased, and the safety and stability are superior to the conventional bicarbonate-containing chemical liquid.

[0024]

EXAMPLES Hereinafter, the present invention will be described in more detail based on examples, comparative examples, and test examples, but the present invention is not limited to these examples.

Example 1 According to the composition shown in Table 1 below, each component of the solution (A) was dissolved in an appropriate amount of distilled water at room temperature, and carbon dioxide gas was blown into the solution to adjust the pH to about 7.4. After adding water for injection to make the total volume 10 L, the mixture was filtered through a membrane filter having a pore size of 0.22 μm. This solution was filled into the I room of a two-compartment polypropylene container in an amount of 500 ml each. On the other hand, according to the composition shown in Table 2 below, each component of the solution (B) was dissolved in an appropriate amount of distilled water, and water for injection was added to make a total volume of 10 L. This solution was filtered in the same manner, and each of the two chambers made of polypropylene was filled with 500 ml each in another chamber.
High-pressure steam sterilization was performed at 20 ° C. for 20 minutes. After cooling the bicarbonate-containing chemical solution container thus obtained to room temperature,
A packaging material (silica-deposited PET / silica-evaporated PET / Nylon / CPP laminate film), and the space between the container and the packaging material is purged with nitrogen using a high-purity nitrogen gas (replacement rate of 95% or more), sealed, and sealed to a plastic container containing a bicarbonate-containing chemical liquid. Was manufactured.

[0026]

[Table 1]

[0027]

[Table 2]

Example 2 The procedure of Example 1 was repeated, except that the space between the container and the packaging material was replaced with an air atmosphere instead of a nitrogen gas atmosphere.
A package of a plastic container containing a bicarbonate-containing drug solution was manufactured.

Example 3 As a deoxidizing agent, "Tamotsu V" (carbon dioxide content: 1.0-4.0 vol%) manufactured by Oe Chemical Co., Ltd. 1.0-8.0 vol%), and the bicarbonate-containing chemical solution was prepared in the same manner as in Example 1, except that the space between the container and the packaging material was replaced with a nitrogen atmosphere and an air atmosphere was used. A package of a filled plastic container was manufactured.

Comparative Example 1 "Ageless ZH" was used in place of "Tamotsu D" as the oxygen scavenger.
A bicarbonate-containing chemical solution was prepared in the same manner as in Example 1 except that a gas atmosphere (manufactured by Mitsubishi Gas Chemical Co., Ltd.) was used and that the space between the container and the packaging material was replaced with a nitrogen atmosphere and an air atmosphere was used. A package of a filled plastic container was manufactured.

Comparative Example 2 "Ageless G" was used in place of "Tamotsu D" as the oxygen scavenger.
(Mitsubishi Gas Chemical Co., Ltd.) was used, and the bicarbonate content was the same as in Example 1 except that the space between the container and the packaging material was replaced with a nitrogen gas atmosphere and an air atmosphere was used. A package of a chemical-filled plastic container was manufactured.

Test Example 1 The packages obtained in Examples 1 to 3 and Comparative Examples 1 and 2 were
It was stored at 0 ° C. and 75% RH for 2 months. The pH and foreign substance inspection were measured for the drug solution in the container housed in the package. The results are shown in Table 3 below.

[0033]

[Table 3]

From Table 3 above, as shown in Example 1,
The chemical solution in which the space between the chemical solution container and the package was replaced with nitrogen using a “Tamots D” type oxygen absorber had the lowest pH change and was stable. Further, as shown in Example 2 or 3, even when the space between the container and the packaging material is air,
When the “Tamots D” type or “Tamots V” type oxygen absorber is used, bicarbonate content is higher than that of Comparative Examples 1 and 2 using conventional iron powder or ascorbic acid oxygen absorbers. It was found that the stability of the drug solution was greatly improved.

[0035]

According to the present invention, since the bicarbonate-containing preparation uses a catechol-based deoxidizing agent that generates a small amount of carbon dioxide gas, the carbon dioxide or oxygen is positively applied to the space between the container and the packaging material from the outside. Even if nitrogen gas is not sealed, it remains in air,
It is possible to maintain the stability of the chemical solution and the efficacy of the oxygen detector. Further, even if a pinhole occurs in the packaging material, when oxygen is mixed in from the outside, the color of the oxygen detecting agent changes before the pH of the chemical solution changes, so that defective products can be identified. . Further, in the present invention, a bicarbonate-containing chemical solution is filled in a plastic container having two chambers, and an oxygen detector is sealed as a pinhole checker in a space between the container and the packaging material. By enclosing the oxygen absorber that is a catechol-based oxygen absorber, a container package filled with a bicarbonate-containing chemical solution that is highly useful in terms of stability and safety of the preparation can be obtained.

 ──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor Satoshi Kono 3-9-3 Honjo Nishi, Kita-ku, Osaka City Inside Nissha Corporation (72) Inventor Makoto Sato 3-9-1, Honjo Nishi, Kita-ku, Osaka City Inside Nissha Corporation (72) Inventor Shinichi Kawamura 3-9-3 Honjo Nishi, Kita-ku, Osaka City Inside Nissha Corporation (72) Seigo Inventor Seigo Kodaira 3-9-1, Honjo Nishi, Kita-ku, Osaka Stock Company Inside Nissha

Claims (6)

[Claims] 1. A plastic container filled with a bicarbonate-containing chemical solution is packaged with a gas-impermeable packaging material, and the space between the plastic container and the packaging material actively adjusts the concentration of carbon dioxide gas. A bicarbonate-containing chemical liquid-filled container package having an atmosphere not subjected to oxygen treatment and further containing a deoxidizer and an oxygen detector in the space. 2. A plastic container filled with a bicarbonate-containing chemical solution is packaged with a gas-impermeable packaging material, and the space between the plastic container and the packaging material is filled with a nitrogen gas atmosphere or actively carbonic acid. A bicarbonate-containing chemical liquid-filled container package having an air atmosphere in which no gas is present, and further containing a deoxidizer and an oxygen detector in the space. 3. The package containing a bicarbonate-containing chemical liquid according to claim 1, wherein the oxygen scavenger is an oxygen scavenger that generates a small amount of carbon dioxide gas. 4. The package according to claim 1, wherein the oxygen absorber is a catechol-based oxygen absorber. 5. A package containing a bicarbonate-containing chemical solution according to claim 1, wherein the bicarbonate-containing chemical solution is a solution containing a bicarbonate and, if necessary, an electrolyte and / or a reducing sugar. 6. The plastic container is a multi-chamber container, wherein the bicarbonate-containing chemical solution has a pH of 7.6 to 6.
A bicarbonate solution (A) of 8.6 and a pH of 3.0 to 3.0;
A solution (B) containing an electrolyte and / or a reducing sugar having a pH of 5.0 and a pH of 7.0 to 7.6 when the solution (A) and the solution (B) are mixed. Yes,
The bicarbonate-containing drug solution-filled container package according to claim 1 or 2, wherein a solution (A) is filled in one chamber and a solution (B) is filled in another chamber in the multi-chamber container.